Introduction of extraneous materials in the form of tattoos and vaccines can induce a cutaneous inflammatory infiltrate that clinically and histologically invoke the possibility of a lymphoproliferative process.^1,2 It has been postulated that delayed hypersensitivity to specific components of the vaccine or tattoo ink may give rise to such immunologic reactions.

The beneficial effects of vaccine-induced immunity outweigh the adverse effects in most people. Most of the local side effects such as pain, swelling, and redness are transient and usually last for a few days after vaccination.³ In rare instances, papules or subcutaneous nodules may develop at the injection site of antigens and persist for months to years; such a response was first documented in 1974 by Bernstein et al.⁴ in a patient receiving hyposensitization injections.

Pseudolymphomas at vaccination sites have been reported more commonly in women.^5,6 The nodules usually develop as early as 1 month after vaccination or may be delayed up to 5 years.⁶ Subcutaneous nodules are the most common presentation of vaccine-associated pseudolymphomas; however, papules and even indurated plaques may be seen as well. Single or multiple lesions may be present and are often accompanied by pruritus, pain, erythema, hyperpigmentation, and hypertrichosis.^{7,8,9,10,11,12} High degree of clinical suspicion with respect to the site of the lesion and history of immunization is essential for the diagnosis and management.

Most of these lesions have developed after injection of vaccines or desensitization solutions that contain aluminum oxyhydroxide as an adjuvant, such as hepatitis B, hepatitis A, early summer meningoencephalitis, varicella-zoster, tetanus, and diphtheria/tetanus.^5,6,8,10,13 The development of a second pseudolymphoma in a patient with prior history after revaccination has been reported. Aluminum adjuvant from the vaccine is present in both the soluble (biologically reactive) form, which associates with antigens, antibodies, and other proteins and diffuses away from the injection site and the insoluble (1 to 20 μm, particulate) form, which persists at the site of injection and functions as a constant source of soluble Al³⁺ ions and antigens.¹⁴ The particulate form of aluminum is phagocytized by macrophages, functions as a constant source of immunologic activation, and may lead to the development of pseudolymphomas in susceptible patients. Whether direct toxic effects of aluminum, a delayed hypersensitivity response through activation of T_H2-mediated response, or both could contribute to the development of pseudolymphomas is unknown.¹⁵

Histologically, a lymphocyte-predominant infiltrate is located mostly within the subcutaneous fat in all cases, and may at times involve the dermal–subcutaneous interface.⁵ The infiltrate is dense and more often nodular than diffuse and is characterized by the presence of predominantly lymphocytes admixed with histiocytes as well as fewer numbers of polyclonal plasma cells and eosinophils (Fig. 47-1A,B). B lymphocyte–predominant germinal centers are frequently seen with variable degrees of interfollicular fibrosis and fat necrosis, which are also highlighted by CD10, CD20, CD79a, CD23, CD21, and BCL-6, but BCL-2 expression is restricted to the interfollicular T cells, which are also positive for CD3, CD5, CD7, and CD43. In addition, perivascular and periadnexal lymphohistiocytic infiltrate and, rarely, a lichenoid infiltrate may also be seen.¹² Molecular analysis reveals polyclonality in both the B and T lymphocytes.

In early lesions, histiocytes with abundant granular amphophilic cytoplasm may be prominent (Fig. 47-1C,D), and may palisade around necrotic debris.^5,6,16 These histiocytes also stain positive with diastase–periodic acid–Schiff stain.¹⁰ The presence of particulate aluminum with the histiocytes can be demonstrated rarely as fine, faintly polarizable material or by treating with hydrochloric acid to remove calcium from the tissue and then with Morin solution, followed by examination using a fluorescence microscope.^6,10 Electron microscopy demonstrates dense needle-shaped crystals within the histiocytes.^6,16 Energy-dispersive x-ray microanalysis can also be used to demonstrate the presence of inorganic aluminum in the tissues.^10,16

In most cases, a contiguous involvement of the underlying skeletal muscle has not been demonstrated. However, in patients with chronic fatigue syndrome (CFS), myalgia, and macrophagic myofasciitis (MMF), a similar inflammatory infiltrate may be present in the perimuscular fat, and focal lymphocytic vasculitis may be identified within the preserved myocyte fibers.⁶

Other injection site nodules include granulomatous reaction to vaccines such as varicella-zoster and bacilli Calmette–Guérin.^17,18 Deep granuloma annulare or rheumatoid nodule–like reactions with prominent necrobiosis, and even lupus profundus–like patterns have also been documented at vaccination sites.¹⁶

Spontaneous resolution of the subcutaneous nodules is not frequent. Intralesional steroid injections and surgical excisions are curative in most patients.⁶ Local radiotherapy has also a role in controlling disease progression.⁵ Topical high-potency steroids and systemic immunomodulators have also been tried. Future avoidance of the causative vaccinations and use of alternate vaccine preparations are also important, along with long-term follow-up.